Type 2 diabetes (T2D) is characterized by insulin resistance and a relative deficiency of insulin secretion. T2D affects ~300 million people worldwide, >25 million in the US alone. 27% of Americans aged e60y suffer from T2D. T2D incidence and prevalence are increasing rapidly. In the US alone, medical costs of diabetes in 2012 were estimated at $176 billion, ~10% of US health care costs. The increasing number of younger T2D cases amplifies the socioeconomic impact of T2D and increases the urgency with which we must act to identify causes and new treatments. The goal of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genetic variants that predispose to T2D and that are responsible for variability in T2D-related QTs. Improved understanding of the genetic basis of T2D and related QTs has the potential to reduce the impact of the T2D epidemic by supporting identification of novel drugs and therapies, enabling better targeting of drugs and therapies, and providing more accurate T2D risk prediction. In this proposal, we propose to (1) discover genetic loci and variants that influence T2D risk and variability in T2D-related QTs using association studies based on GWAS and sequence data with increasing emphasis on low-frequency and rare variants; (2) identify muscle and adipose tissue regulatory elements that increase risk of T2D and contribute to variation in related QTs by molecularly characterizing muscle and adipose biopsy samples from 324 individuals from across the glucose tolerance spectrum; and (3) identify the likely causal genes (and other functional units) and disease mechanisms at known T2D and QT loci through genotype-based callback detailed phenotyping in appropriately consented individuals with likely high-impact variants and in non-carrier controls. These efforts will contribute to improved understanding of the etiology of T2D, and have the potential to point the way to novel methods of treatment and prevention. Methods developed and lessons learned in the FUSION study will be useful in the study of other complex genetic diseases.